Acetal hydrazones of 2-hydrazino-3H-1,4-benzodiazepine

ABSTRACT

Compounds of the formula: ##STR1## wherein R 1  is alkyl of 1 to 3 carbon atoms, inclusive; wherein R 2  is hydrogen, methyl or ethyl; wherein R 3  is hydrogen, fluoro, chloro, bromo, nitro and --CF 3  ; and wherein A is phenyl, o-chlorophenyl, o-fluorophenyl, 2,6-difluorophenyl, and 2-pyridyl, are prepared by treating a hydrazino compound of the formula: ##STR2## with a carbonyl compound II: ##STR3## wherein R 1  is defined as above, and R&#39;, R&#34; are alkyl of 1 to 3 carbon atoms, inclusive or the group ##STR4## is a cyclic acetal to give a compound of formula III: ##STR5## wherein R 1 , R 2 , R 3 , R&#39;, R&#34; and Ar are defined as above, and cyclizing compound III to give the compound IV above. 
     Compounds III and IV, including the pharmacologically acceptable acid addition salt of these compounds, have sedative, anxiolytic and muscle-relaxing activity and can be used for the treatment of anxieties or muscle strains of mammals, including man.

This is a division of application Ser. No. 775,887 filed Mar. 9, 1977.

BACKGROUND OF THE INVENTION Field of the Invention

The novel compounds and process of production therefor can beillustratively represented as follows: ##STR6## wherein R', R" are alkylof 1 to 3 carbon atoms, inclusive, or the group ##STR7## together is##STR8## wherein R₁ is alkyl of 1 to 3 carbon atoms, inclusive; whereinR₂ is hydrogen, methyl or ethyl; wherein R₃ is hydrogen, fluoro, chloro,bromo, nitro and -CF₃ ; and wherein Ar is phenyl, o-chlorophenyl,o-fluorophenyl, 2,6-difluorophenyl, and 2-pyridyl.

The process of this invention comprises: treating a hydrazino compoundof formula I with a carbonyl reagent of formula II to obtain acorresponding compound of formula III; and treating compound III with acyclizing reagent to obtain the corresponding compound of formula IV.

The invention claims the compounds of formulae III and IV, the processto make these compounds and the pharmacologically acceptable acidaddition salts thereof.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Alkyl groups of 1 to 3 carbon atoms, inclusive, are exemplified bymethyl, ethyl, propyl and isopropyl.

The more preferred compounds of this invention are of the formula IIIAand IVA; ##STR9## wherein R₁ ' is methyl or ethyl; wherein R₃ ' isfluoro, chloro, bromo, or trifluoromethyl; wherein R_(o) ' is alkyl of 1to 3 carbon atoms, inclusive; and wherein Ar is phenyl, o-chlorophenyl,o-fluorophenyl, 2,6-difluorophenyl or 2-pyridyl, and thepharmacologically acceptable acid addition salts thereof.

The most preferred compounds of this invention are of the formula IIIBand IVB; ##STR10## wherein R₃ " is fluoro, chloro or trifluoromethyl,and wherein R₄ is hydrogen, chloro or fluoro, and the pharmacologicallyacceptable acid addition salts thereof.

Compounds of formula III and IV (including IIIA, IIIB, and IVA and IVB)are sedative, tranquilizing, anxiolytic, muscle-relaxing andanti-convulsive agents which are useful for treating anxieties,convulsions or strained muscles in mammals, including man.

The sedative-tranquilizing-anxiolytic activity was evaluated incompounds of formula III and IV by the following test:

Gamma Butyrolactone Sleep Potentiation

Gamma butyrolactone produces loss of righting in mice at doses higherthan 400 mg./kg. intraperitoneally. At lower doses (200 mg./kg.) themice do not lose their righting reflex unless previously treated withsub-hypnotic doses of central nervous system depressant agents. Thisthen provides a technique to study the depressant activity of potentialcentral nervous system agents.

Method

The test compound is injected intraperitoneally 50 mg./kg. into a groupof four mice and thirty minutes later gamma-butyrolactone is injectedintraperitoneally, 200 mg./kg. (normally a sub-hypnotic dose). After tenminutes, the mice are tested for loss of righting reflex. If more thantwo mice show a loss of righting for one minute or more, the compound isretested at multiple dose levels.

Anti-convulsion Test

Protection Against Bicucullin-Induced Tonic Extensor Convulsions

In this procedure, groups of four Carworth Farms male mice, weighing18-22 g. each, are injected intraperitoneally with the test agentprepared in 0.25% methylcellulose. Thirty minutes later, bicucullin isinjected intravenously at 1 mg./kg. Bicucullin is solubilized in 1Nhydrochloric acid and diluted to a concentration of 1-4 mg./ml. withphysiological saline and adjusted to a final pH of 5-6 before injection.Mice are observed for 5 minutes after bicucullin injection. A compoundis considered to be active if it protects at least 2 of the 4 mice fromtonic extensor convulsions during this period. Active compounds areretested using multiple dose levels decreasing at 0.3 or 0.5 logintervals and the number of mice failing to convulse is used as aquantal response to calculate the ED₅₀ (Spearman and Karber: Finney,D.J., Statistical Method in Biological Assay, Hafner Publ. Co., N.Y., p.524, 1952). This procedure is a useful test for detecting compounds withminor tranquilizer or sedative activity.

Anti-convulsant, Muscular Relaxing Activity by the Pentylenetetrazol(Metrazol) Test

Metrazol Induced Convulsion Test

The test compound is injected intraperitoneally (50 mg./kg.) into groupsof four mice at multiple dose levels decreasing in 0.3 log intervals.Thirty minutes later Metrazol is injected subcutaneously (at the nape ofthe neck), 85 mg./kg. Fifteen minutes later a set of keys is rattledover the cage to induce the clonic convulsions. The number of miceprotected against convulsions and death is recorded.

Thus, these compounds are useful for tranquilization, sedation, treatinganxieties, and also useful as anti-convulsant and muscle relaxants inmammals and birds.

The pharmaceutical forms contemplated by this invention includepharmaceutical compositions suited for oral, parenteral, and rectal use,e.g., tablets, powder packets, cachets, dragees, capsules, solutions,suspensions, sterile injectable forms, suppositories, bougies, and thelike. Suitable diluents or carriers, such as carbohydrates (lactose),proteins, lipids, calcium phosphate, corn starch, stearic acid,methylcellulose and the like may be used as carriers or for coatingpurposes. Water or oil, e.g., coconut oil, sesame oil, safflower oil,cottonseed oil, peanut oil, may be used for preparing solutions orsuspensions of the active drug. Sweetening, coloring and flavoringagents may be added.

For mammals and birds, food premixes with starch, oatmeal, driedfishmeat, fishmeal, flour and the like can be prepared.

The compounds of formulae III and IV can be used in dosages of 0.05-1mg./kg./day; preferably in unit dosages of 0.1-1 mg./kg./day in oral orinjectable preparations as described above, to alleviate tension andanxiety, muscle spasm or convulsions in mammals, or birds, such as e.g.,occurs when animals are in travel.

The starting materials of formula I of this invention, a 5-phenyl- orsubstituted phenyl group, are known in the art, e.g., from Canadian Pat.No. 908,657.

The compounds of formula I which have a 2-pyridyl group in the5-position can be made from the corresponding 2-thiones according toU.S. Pat. No. 3,996,230.

In carrying out the process of this invention, a compound of formula Iis reacted with a carbonyl compound of formula II. The reaction isgenerally carried out in an organic solvent, inert in this reaction,e.g., dioxane, tetrahydrofuran, diethyl ether, ethanol, benzene,toluene, or the like. The type of carbonyl compound selected depends onthe alkyl group desired in position 2 of final compounds of formula IV.1,1-Dialkoxy- 2-propanone provides a 2-methyl group in compounds offormula IV, the 2-butanones provide an ethyl group and the 2-pentanonesare productive of a propyl group in the 2-position. The alkoxy groups inthese 1,1-dialkoxy-2-alkanones can be methoxy, ethoxy, or propoxy, withmethoxy preferred. In the preferred embodiment of this invention, thealkanone II is used in a stoichiometric excess like 1,5 to 5 times thecalculated equimolar amount to one mole equivalent of the hydrazinocompound I. The temperature of the reaction is between 10°-50° C.,preferably room temperature, and the reaction period is between 2- 48hours, with 12 to 24 hours usually sufficient at room temperature (20°to 25° C.). After termination of the reaction, the product (III) isisolated and purified in conventional manner, such as by precipitationand filtration, extraction, chromatography and recrystallization.

Compound III is cyclized to give compound IV with concentrated sulfuricacid (neat), sulfuric acid in Sulfolane, or anhydrous hydrogen fluoride,with concentrated sulfuric acid preferred. Low temperatures (-20° to+10° C. at the start with 10° to 40° C. in the later stage) arepreferred for this reaction. The reaction period is between 1/2 to 6hours, with 1 to 4 hours being usually sufficient. Thereafter thereaction mixture is neutralized and the product IV is obtained byextraction. Compound IV is purified in conventional manner, e.g.,chromatography and recrystallizations.

The following Preparation and Examples are illustrative of the processand the compounds of the present invention, but are not to be construedto be limiting.

In the manner given in U.S. Pat. No. 3,996,2301,3-dihydro-2-hydrazino-5-(2-pyridyl)-2H-1,4-benzodiazepines can beprepared. Representative compounds, thus prepared, include:7-chloro-1,3-dihydro-2-hydrazino-5-(2-pyridyl)-2H-1,4-benzodiazepine,7-fluoro-1,3dihydro-2-hydrazino-5-(2-pyridyl)-2H-1,4-benzodiazepine,7nitro-1,3-dihydro-2-hydrazino-5-(2-pyridyl)2H-1,4-benzodiazepine,8bromo-1,3-dihydro-2-hydrazino-5-(2-pyridyl)-2H-1,4-benzodiazepine,8-fluoro-1,3-dihydro-2-hydrazino-5(2-pyridyl)-2H-1,4-benzodiazepine,8-chloro-1,3-dihydro-2-hydrazino-5-(2-pyridyl)-2H-1,4-benzodiazepine,9trifluoromethyl-1,3-dihydro-2-hydrazino5-(2pyridyl)-2H-1,4-benzodiazepine,9bromo-1,3-dihydro-2-hydrazino-5-(2-pyridyl)-2H-1,4-benzodiazepine,8-nitro-1,3-dihydro-2-hydrazino-5-(2-pyridyl)-2H-1,4-benzodiazepine,9-nitro-1,3-dihydro-2-hydrazino-5-(2-pyridyl)-2H-1,4-benzodiazepine,7-trifluoromethyl-1,3-dihydro-2-hydrazino-5-(2-pyridyl)-2H-1,4-benzodiazepine,and the like.

EXAMPLE 1 1,1-Dimethoxy-2-propanone,2-(7-chloro-5-phenyl-3H-1,4-benzodiazepin-2-yl)hydrazone

A solution of 2.84 g. (0.01 mole) of7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine and 2.6 g. (0.022mole) of 1,1-dimethoxy-2-propanone in 100 ml. of tetrahydrofuran wasstirred at room temperature for 18 hours and evaporated in vacuo. Theresidue was dissolved in methylene chloride, washed with water and driedover anhydrous sodium sulfate. After filtraton and concentration theproduct was chromatographed on silica gel, eluting with a mixture ofhexane 22% methylene chloride 76% and 2-propanol 2%. The product wascrystallized from a mixture of ethyl acetate and hexane yielding 2.3 g.(60%) of 1,1-dimethoxy-2-propanone,2-(7-chloro-5-phenyl-3H-1,4-benzodiazepin-2-yl)hydrazone of meltingpoint 182°-183° C.

Anal. Calcd. for C₂₀ H₂₁ ClN₄ O₂ : C, 62.41; H, 5.50; Cl, 9.21; N,14.56. Found: C, 62.62; H, 5.55, Cl, 9.16; N, 14.72.

EXAMPLE 29-Chloro-1,5-dihydro-2-methyl-7-phenyl-as-triazino[4,3-a][1,4]benzodiazepin-1-ol

To 15 ml. of concentrated sulfuric acid, at 0° C. under nitrogen, wasslowly added with stirring 2.52 g. (0.065 mole) of1,1-dimethoxy-2-propanone,2-(7-chloro-5-phenyl-3H-1,4-benzodiazepine-2-yl)hydrazone. The solutionwas allowed to warm to room temperature, stirred for 2 hours, quenchedwith ice and aqueous sodium bicarbonate solution, and extracted withmethylene chloride. After washing with water, drying over anhydroussodium sulfate and evaporating in vacuo the residue was crystallizedfrom a mixture of methylene chloride, methanol and ethyl acetate. Moreproduct was obtained by chromatographing the filtrate on silica gel,eluting with 10% (volume) methanol in chloroform and crystallizing fromethyl acetate. The total yield was 1.15 g. (about 50%) of9-chloro-1,5-dihydro-2-methyl-7phenyl-as-triazino-[4,3-a][1,4]benzodiazepin-1-olof melting point 170°-172° C. (dec.), containing ethyl acetate. Thecompound seems to solvate with many solvents and the decompositionpoints varied widely. A sample for analysis was crystallized from ethylacetate-methanol and was found to contain about 0.8 mole of methanoleven after long drying in vacuo, melting point 170°-1/4° C. (dec.).

Anal. Calcd. for C₁₈ H₁₅ ClN₄ 0.sup.. 0.8 CH₃ OH: C, 61.96; H, 5.03, Cl,9.73; N, 15.37; MeOH, 7.03. Found: C, 61.54; H, 5.02; Cl, 9.73, N,15.69; melt solvate), 6.81 (MeOH).

EXAMPLE 31,1-Dimethoxy-2-propanone,2-[7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone

Following Example 1, 15.96 g. (0.05 mole) of7-chloro-5-(o-chlorophenyl)-2-hydrazino-3H-1,4-benzodiazepine and 11.8g. (0.1 mole) of 1,1-dimethoxy-2-propanone in 250 ml. of tetrahydrofuranwere reacted together. The product was crystallized from ethylacetate-hexane and additional material was obtained by chromatographingthe filtrate on silica gel, eluting with 5% methanol in chloroform. Thetotal yield was 17.0 g. (81%) of 1,1-dimethoxy-2-propanone,2-[7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]-hydrazone ofmelting point 153°-158° C. The sample for analysis, recrystallized fromethyl acetate-hexane, had a melting point of 157°-158° C.

Anal. Calcd. for C₂₀ H₂₀ Cl₂ N₄ O₂ : C, 57.28; H, 4.81; Cl, 16.91; N,13.36. Found: C, 57.55; H, 4.95, Cl, 16.95; N, 13.20.

EXAMPLE 49-Chloro-7-(o-chlorophenyl)-1,5-dihydro-2-methyl-as-triazino4,3-a][1,4]benzodiazepin-1-ol

Following Example 2, 7.57 g. (0.018 mole) of 1,1-dimethoxy-2-propanone,2-[7-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone and30 ml. of concentrated sulfuric acid were reacted. The product wascrystallized from ethyl acetate yielding 4.08 (60%) of crystallinesolid, 9-chloro-7-(o-chlorophenyl)- 1,5-dihydro-2-methyl-as-triazino[4,3-a][1,4]benzodiazepin-1-ol of melting point170°-173° C. (dec.). A nuclear magnetic resonance spectrum showed thepresence of ethyl acetate of crystallization. A sample for analysis wascrystallized from a mixture of ethyl acetate and methylene chloride,melting point 165°-170° C. (dec.).

Anal. Calcd. for C₁₈ H₁₄ Cl₂ N₄ O· 0.08 E tOAc· 0.04 Ch₂ Cl₂ : C, 57.62;H, 3.87; Cl, 19.01, N, 14.64; EtOAc, 1.84; Ch₂ Cl₂, 0.89. Found: C,57.00; H, 3.72; Cl, 18.58; N, 14.71; melt solvate EtOAc, 1.68; CH₂ Cl₂,0.82.

EXAMPLE 5 1,1-Diethoxy-2-butanone,2-[7-fluoro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone

In the manner given in Example 1,7-fluoro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can bereacted with 1,1-diethoxy-2-butanone in tetrahydrofuran to give1,1-diethoxy-2-butanone,2-[7-fluoro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone.

EXAMPLE 69-Fluoro-1,5-dihydro-2-ethyl-7-(o-chlorophenyl)-as-triazino4,3-a][1,4]benzodiazepin-1-ol

In the manner given in Example 2, 1,1-diethoxy-2-butanone 2-[7-fluoro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone can betreated at 0°C. under nitrogen with concentrated sulfuric acid to give9-fluoro-1,5-dihydro-2-ethyl-7-(o-chlorophenyl)-as-triazino[4,3-a][1,4]benzodiazepin-1-ol.

EXAMPLE 7 1,1-Dimethoxy-2-propanone,2-[7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]hydrazone

In the manner given in Example 1, 7-bromo-2-hydrazino-5-(2-pyridyl)-3H-1,4-benzodiazepine can be reacted with 1,1-dimethoxy-2-propanone intetrahydrofuran to give 1,1-dimethoxy-2-propanone,2-[7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]hydrazone.

EXAMPLE 89-Bromo-1,5dihydro-2-methyl-7-(2-pyridyl)-as-triazino[4,3-a][1,4]benzodiazepin-1-ol

In the manner given in Example 2, 1,1-dimethoxy-2-propanone,2-[7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]hydrazone can betreated at 0° C. under nitrogen with concentrated sulfuric acid to give9-bromo-1,5-dihydro-2-methyl-7-(2-pyridyl)-as-triazino[4,3-a][1,4]benzodiazepin-1-ol.

EXAMPLE 9 1,1-Dipropoxy-2-pentanone,2-(7-trifluoromethyl-5-phenyl-3H-1,4-benzodiazepin-2-yl)hydrazone

In the manner given in Example 1,7-trifluoromethyl-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can bereacted with 1,1-dipropoxy-2-pentanone in tetrahydrofuran to give1,1-dipropoxy-2-pentanone,2-(7trifluoromethyl-5-phenyl-3H-1,4-benzodiazepin-2-yl)hydrazone.

EXAMPLE 109-Trifluoromethyl-1,5-dihydro-2-propyl-7-phenyl-as-triazino[4,3-a][1,4]benzodiazepin-1-ol

In the manner given in Example 2, 1,1-diproproxy-2-pentanone,2-(7-trifluoromethyl-5-phenyl-3H-1,4-benzodiazepin-2-yl)hydrazone can betreated at 0° C. under nitrogen with concentrated sulfuric acid to give9-trifluoromethyl-1,5-dihydro-2-propyl-7-phenyl-as-triazino-[4,3-a][1,4]benzodiazepin-1-ol.

EXAMPLE 11 1,1-Dimethoxy-2-propanone, 2-[5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone

In the manner given in Example 1,2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be reacted with1,1 -dimethoxy-2-propanone in tetrahydrofuran to give1,1-dimethoxy-2-propanone,2-[5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone.

EXAMPLE 127-(o-Chlorophenyl)-1,5-dihydro-2-methyl-as-triazino[4,3-a][1,4]benzodiazepin-1-ol

In the manner given in Example 2, 1,1-dimethoxy-2-propanone,2-[5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone can be treatedat 0° C. under nitrogen with concentrated sulfuric acid to give7-(o-chlorophenyl)-1,5-dihydro-2-methyl-as-triazino[4,3-a][1,4]benzodiazepin-1-ol.

Example 13 1,1-Diethoxy-2-propanone,2-[7-nitro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone

In the manner given in Example 1,7-nitro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can bereacted with 1,1-diethoxy-2-propanone in tetrahydrofuran to give1,1-diethoxy-2-propanone,2-[7-nitro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone.

EXAMPLE 149-Nitro-1,5-dihydro-2-methyl-7-(o-chlorophenyl)-as-trizino[4,3-a][1,4]benzodiazepin-1-ol

In the manner given in Example 2, 1,1-diethoxy-2-propanone,2-[7-nitro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone can betreated at 0° C. under nitrogen with concentrated sulfuric acid to give9-nitro-1,5-dihydro-2-methyl-7-(o-chlorophenyl)-as-triazino-[4,3-a][1,4]benzodiazepin-1ol.

EXAMPLE 15 1,1-Dimethoxy-2-butanone,2-[7-chloro-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone

In the manner given in Example 1,7-chloro-2-hydrazino-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine can bereacted with 1,1-dimethoxy-2-butanone in tetrahydrofuran to give1,1-dimethoxy-2-butanone,2-[7-chloro-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone.

EXAMPLE 169-Chloro-1,5-dihydro-2-ethyl-7-(2,6-difluorophenyl)-as-triazino[4,3-a][1,4]benzodiazepin-1-ol

In the manner given in Example 2, 1,1-dimethoxy-2-butanone,2-[7-chloro-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazonecan be treated at 0° C. under nitrogen with concentrated sulfuric acidto give 9-chloro-1,5-dihydro-2-ethyl-7-(2,6-difluorophenyl)-as-triazino[4,3-a][1,4]benzodiazepin-1-ol.

EXAMPLE 17 1,1-Dimethoxy-2-pentanone,2-[6-bromo-5-(o-fluorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone

In the manner given in Example 1,6-bromo-2-hydrazino-5-(o-fluorophenyl)-3H-1,4-benzodiazepine can bereacted with 1,1-dimethoxy-2-pentanone in tetrahydrofuran to give1,1-dimethoxy-2-pentanone,2-[6-bromo-5(o-fluorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone.

EXAMPLE 188-Bromo-1,5-dihydro-2-propyl-7-(o-fluorophenyl)-as-triazino[4,3a][1,4]benzodiazepin-1-ol

In the manner given in Example 2, 1,1-dimethoxy-2-pentanone,2-[6-bromo-5-(o-fluorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone can betreated at 0° C. under nitrogen with concentrated sulfuric acid to give8-bromo-1,5-dihydro-2-propyl-7-(o-fluorophenyl)-as-triazino[4,3-a][1,4]benzodiazepin-1-ol.

EXAMPLE 19 1,1-Dimethoxy-2-butanone,2-[8-fluoro-5-phenyl-3H-1,4-benzodiazepin-2-yl]hydrazone

In the manner given in Example 1,8-fluoro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be reacted with1,1-dimethoxy-2-butanone in tetrahydrofuran to give 1,1-dimethoxy-Lb2-butanone, 2-(-dimethoxy--fluoro-5-phenyl-3H-1,4-benzodiazepin-2-lyl)hydrazone.

EXAMPLE 2010-Fluoro-1,5-dihydro-2-ethyl-7-phenyl-as-triazino[4,3-a][1,4]benzodiazepin-1-ol

In the manner given in Example `, 1,1-dimethoxy-2-butanone,2-(8-fluoro-5phenyl-3H-1,4-benzodiazepin-2-yl)hydrazone can be treatedat 0° C. under nitrogen with concentrated sulfuric acid to give10-fluoro-1,5-dihydro-2-ethyl-7-phenyl-as-triazino[4,3-a][1,4]benzodiazepin-1-ol.

EXAMPLE 21 1,1-Diethoxy-2-propanone,2-[8-chloro-5-(o-chlorophenyl]-3H-1,4-benzodiazepin-2-yl]hydrazone

In the manner given in Example 1,8-chloro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can bereacted with 1,1-diethoxy-2-propanone in tetrahydrofuran to give1,1-diethoxy-2-propanone,2-[8-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone.

EXAMPLE 2210-Chloro-1,5-dihydro-2-methyl-7-(o-chlorophenyl)-as-triazino[4,3-a][1,4]benzodiazepin-1-ol

In the manner given in Example 2, 1,1-diethoxy-2-propane,2-[8-chloro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone canbe treated at 0° C. under nitrogen with concentrated sulfuric acid togive 10-chloro-1,5-dihydro-2-methyl7-(o-chlorophenyl)-as-triazino[4,3-a][1,4]benzodiazepin-1-ol.

EXAMPLE 23 1,1-Dimethoxy-2-propanone,2-[7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]- -dihydro-hydrazone

In the manner given in Example 1,2-hydrazino-5-(2-pyridyl)-3H-1,4-benzodiazepine can be reacted with1,1-dimethoxy-2-propanone in tetrahydrofuran to give1,1-dimethoxy-2-propanone,2-[7-chlprp-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]hydrazone.

EXAMPLE 249-Chloro-1,5-dihydro-2-methyl-7-(2-pyridyl)-as-triazino[4,3-a][1,4]benzodiazepin-1-ol

In the manner given in Example 2, 1,1-dimethoxy-2-propanone,2-[7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]hydrazone can betreated at 0° C. under nitrogen with concentrated sulfuric acid to give9-chloro-1,5-dihydro-2-methyl-7-(2-pyridyl)-as-triazino[4,3-a][1,4]-benzodiazepin-1-ol.

EXAMPLE 25 1,1-Diethoxy-2-propanone,2-[9-trifluoromethyl-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]hydrazone

In the manner given in Example 1,9-trifluoromethyl-2-hydrazino-5-(2-pyridyl)-3H-1,4-benzodiazepine can bereacted with 1,1-diethoxy-2-propanone in tetrahydrofuran to give1,1-diethoxy-2-propanone,2-(9-trifluoromethyl-5-(2-pyridyl-3H-1,4-benzodiazepin-2-yl)hydrazone.

EXAMPLE 2611-Trifluoromethyl-1,5-dihydro-2-methyl-7-(2-pyridyl)-as-triazino[4,3-][1,4]benzodiazepin-1-ol

In the manner given in Example 2, 1,1-diethoxy-2-propanone,2-[9-trifluoromethyl-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]hydrazonecan be treated at 0° C. under nitrogen with concentrated sulfuric acidto give11-trifluoromethyl-1,5-dihydro-2-methyl-7-(2-pyridyl)-as-triazino[4,3-a][1,4]benzodiazepin-1-ol.

In the manner given in Example 1, other 1,1-dialkoxy-2-alkanone,2-(5-aryl-3H-1,4-benzodiazepin-2-yl)hyrdrazones of formula III can besynthesized by reacting a selected2-hydrazino-5-aryl-3H-1,4-benzodiazepine I ) with a selected alkanone offormula III. Representative compounds, that can be thus produced,include: 1,1-dipropoxy-2-propanone,2-[7-trifluoromethyl-(o-fluorophenyl)-3H-1,4-benzodiazepin-2-yl]-hydrazone;1,1-dimethoxy-2-propanone,2-[8-trifluoromethyl-5-(o-fluorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone;1,1-diethoxy-2-butanone,2-(9-bromo-5-phenyl-3H-1,4-benzodiazepin-2-yl)hydrazone;1,1-diethoxy-2-pentanone,2-[6-chloro-5-(o-chloropehnyl)-3H-1,4-benzodiazepin-2-yl]hydrazone;1,1-diethoxy-2-butanone,2-[7-nitro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone;1,1-dimethoxy-2-pentanone, 2-(9-nitro-5-phenyl-3H-1,4-yl)hydrazone;2yl)hydrazone; 1,1-dipropoxy-2-butanone,2-[8-bromo-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone;1,1-dimethoxy-2-butanone,2-[6-chloro-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone;1,1-diethoxy-2-butanone,2-[6-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]-hydrazone;1,1-dipropoxy-2-pentanone,2-[8-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]hydrazone;1,1-dimethoxy-2-butanone,2-[6-trifluoromethyl-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]hydrazone;1,1-diethoxy-2-butanone,2-[6-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]hydrazone;1,1-diethoxy-2-pentanone,2-[6-nitro-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]hydrazone;1,1-dipropoxy-2-butanone,2-[8-nitro-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]hydrazone; and thelike.

In the manner given in Example 2, other1,5-dihydro-2-alkyl-7-phenyl-as-triazino[4,3-a][1,4]benzodiazepin-1-ols(IV) can be synthesized by reacting a selected 1,1-dialkoxy-2-alkanone,2-(5-aryl-3H-1,4-benzodiazepin-1-yl)hydrazone (III) with concentratedsulfuric acid. Representative compounds, that can be thus obtained,include:9-trifluoromethyl-1,5-dihydro-2-methyl-7-(o-fluorophenyl)-as-triazino4,3-a][1,4]benzodiazepin-1-ol;10-trifluoromethyl-1,5-dihydro-2-methyl-7-(o-fluorophenyl)-as-triazino-[4,3-a][1,4]benzodiazepin-1-ol;11-bromo-1,5-dihydro-2-ethyl-7-phenyl-as-triazino[4,3-a][1,4]benzodiazepin-1-ol;8-chloro-1,5-dihydro-2-propyl-7-(o-chlorophenyl)-as-triazino[4,3-a][1,4]benzodiazepin-1-ol;9-nitro-1,5-dihydro-2:ethyl-7-(o-chlorophenyl)-as-triazino[4,3-a][1,4]-benzodiazepin-1-ol;11-nitro-1,5-dihydro-2-propyl-7-phenyl-as-triazino[4,3-a][1,4]benzodiazepin-1-ol;10-bromo-1,5-dihydro:2-ethyl-7-(2,6-difluorophenyl)-as-triazino4,3-a]-[1,4]benzodiazepin-1-ol;8-chloro-1,5-dihydro-2-ethyl-7-(2,6-difluorophenyl)-as-triamino[4,3-a][1,4]benzodiazepin-1-ol;8-bromo-1,5-dihydro-2-ethyl-7-(2-pyridyl)-as-triazino[4,3-a][1,4]benzodiazepin-1-ol;10-bromo-1,5-dihydro-2-propyl-7-(2-pyridyl)-as-triazino[4,3-a][1,4]-benzodiazepin-benzodiazepin--ol;8-trifluoromethyl-1,5-dihydro-2-ethyl-7-(2-pyridyl)-as-triazino[4,3-a][1,4]benzodiazepin-1-ol;8-chloro-1,5-dihydro-2-ethyl-7-(2-pyridyl)-as-triazino[4,3-a][1,4]benzodiazepin-1-ol;11-nitro-1,5-dihydro-2-propyl-7-(2-pyridyl)-as-triazino[4,3-a][1,4]benzodiazepin-1-ol,10-nitro-1,5-dihydro-2-ethyl-7-(2-pyridyl)-as-triazino[4,3-a][1,4]benzodiazepin-1-ol;and the like.

Treating the compounds of formula IV with pharmacologically acceptableacids such as hydrochloric, hydrobomic, phosphoric, sulfuric, acetic,propionic, toluenesulfonic, methanesulfonic, tartaric, citric, lactic,malic, maleic, and cyclohexanesulfamic acids produces thepharmacologically acceptable salts of these compounds of formula IVwhich can be used like the free base compounds of formula IV. Saltformation is achieved in conventional manner by reacting the compoundsof formula IV with excess of a selected acid in a suitable medium, e.g.,water, a lower alkanol, ether or acetone and recovering the salt byevaporating the solvent, preferably in vacuo.

I claim:
 1. A compound of the formula III: ##STR11## wherein R' and R"are alkyl of 1 to 3 carbon atoms, inclusive, or the group ##STR12##wherein R₁ is alkyl of 1 to 3 carbon atoms, inclusive; wherein R₂ ishydrogen, methyl or ethyl; wherein R₃ is hydrogen, fluoro, chloro,bromo, nitro and --CF₃ ; and wherein Ar is phenyl, o-chlorophenyl,2,6-difluorophenyl, and 2-pyridyl, and the pharmacologically acceptableacid addition salts thereof.
 2. A compound according to claim 1 whereinR', R" and R₁ are methyl, R₂ is hydrogen, R₃ is 7-bromo, Ar is2-pyridyl, and the compound is therefore 1,1-dimethoxy-2-propanone,2-[7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl]hydrazone.
 3. Acompound according to claim 1 of formula IIIA: ##STR13## wherein R₁ ' ismethyl or ethyl; wherein R₃ ' is fluoro, chloro, bromo, ortrifluoromethyl; wherein R₀ ' is alkyl of 1 to 3 carbon atoms,inclusive; and wherein Ar is phenyl, o-chlorophenyl, o-fluorophenyl,2,6-difluorophenyl or 2-pyridyl, and the pharmacologically acceptableacid addition salts thereof.
 4. A compound according to claim 1 offormula IIIB; ##STR14## wherein R₃ " is fluoro, chloro ortrifluoromethyl, and wherein R₄ is hydrogen, chloro or fluoro, and thepharmacologically acceptable acid addition salts thereof.
 5. A compoundaccording to claim 4 wherein R₃ " is chloro, R₄ is hydrogen and thecompound is therefore 1,1-dimethoxy-2-propanone,2-(7-chloro-5-phenyl-3H-1,4-benzodiazepin-2-yl)hydrazone.
 6. A compoundaccording to claim 4, wherein R₃ " and R₄ are chloro and the compound istherefore 1,1-dimethoxy-2-propanone,2-[7-chloro-5-(o-chlorophenyl)-3h-1,4-benzodiazepin-2-yl]hydrazone.
 7. Acompound according to claim 4, wherein R₃ " is hydrogen, R₄ is chloroand the compound is therefore 1,1-dimethoxy-2-propanone,2-[5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone.
 8. A compoundaccording to claim 4 wherein R₃ " is fluoro, R₄ is chloro and thecompound is therefore 1,1-dimethoxy-2-propanone,2-[7-fluoro-5-(o-chlorophenyl)-3H-1,4-benzodiazepin-2-yl]hydrazone.